ethyl 5-methyl-2,4-dioxohexanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of aniline (0.50 g, 5.4 mmole) and concentrated HCl (0.46 ml) in ethanol (2.5 ml) was added ethyl 5-methyl-2,4-dioxohexanoate (1.0 g, 5.4 mmole) and paraformaldehyde (0.25 g). After heating at reflux over 3 hours hot acetone (13 ml) was added and the resulting solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and extracted with methylene chloride. The aqueous layer was acidified to pH 1 with 3N HCl, extracted with methylene chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from 10% ether in pet. ether gives 0.42 g of the title compound as a pale yellow solid. M.P. 162°-170° C.; 1H NMR (250 MHz, CDCl3) δ1.21 (d, J=6.8 Hz, 6H), 3.24 (heptet, J=6.8 Hz, 1H), 4.52 (s, 2H), 7.23 (m, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.77 (d, J=7.8 Hz); MS m/z 246. After heating was added concentrated under reduced pressure The residue was dissolved in 1N NaOH extracted with methylene chloride extracted with methylene chloride dried over sodium sulfate filtered concentrated under reduced pressure Recrystallization from 10% ether in pet. ether

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-hydrazinyl-2,4-dimethoxypyrimidine (Step 46.8) (140 g, 823 mmol) was dissolved in toluene (3 L) under nitrogen atmosphere and ethyl-2,4-dioxo-5-methylhexanoate (230 g, 1234 mmol) was added dropwise over 15 min. The reaction mixture was heated up and stirred at 110° C. for 1 hr. The brown solution was quenched with saturated aq. NaHCO3 solution (2 L) and extracted with EtOAc (2×2 L). The combined organic layers were washed with brine (2 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was stirred in hexane (1 L) at RT and the resulting suspension was filtrated off and dried to afford the title product (193 g, 596 mmol, 72% yield) as white crystals. tR: 1.01 min (LC-MS 1); ESI-MS: 321 [M+H]+ (LC-MS 1). The reaction mixture was heated up The brown solution was quenched with saturated aq. NaHCO3 solution (2 L) extracted with EtOAc (2×2 L) The combined organic layers were washed with brine (2 L) dried over Na2SO4 filtered concentrated under reduced pressure The crude material was stirred in hexane (1 L) at RT the resulting suspension was filtrated off dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxyphenylhydrazine (14.07 g, 81 mmol) in EtOH (100 mL) was added dropwise to a refluxing solution of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (10 g, 53.7 mmol) in toluene (100 mL), under an argon atmosphere. The reaction mixture was stirred for 18 h at 100° C., allowed to cool to rt, concentrated, diluted with a saturated aqueous solution of sodium bicarbonate (250 mL), and extracted with EtOAc. The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3) to provide 10.1 g of the title compound. tR: 1.11 min (LC-MS 4); to cool to rt concentrated diluted with a saturated aqueous solution of sodium bicarbonate (250 mL) extracted with EtOAc The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxyphenylhydrazine (14.07 g, 81 mmol) in EtOH (100 mL) was added dropwise to a refluxing solution of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (10 g, 53.7 mmol) in toluene (100 mL), under an argon atmosphere. The reaction mixture was stirred for 18 h at 100° C., allowed to cool to rt, concentrated, diluted with a saturated aqueous solution of sodium bicarbonate (250 mL), and extracted with EtOAc. The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3) to provide 10.1 g of the title compound. tR: 1.11 min (LC-MS 4); to cool to rt concentrated diluted with a saturated aqueous solution of sodium bicarbonate (250 mL) extracted with EtOAc The organic extracts were washed with a saturated aqueous solution of sodium bicarbonate dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→7:3)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester (5.6 g, 36.4 mmol) was added to a solution of 4-methoxybenzyl amine (5 g, 36.4 mmol) in acetic acid (40 mL). The mixture was stirred for 10 min at rt. 4-Chloro-2-methylbenzaldehyde (6.77 g, 36.4 mmol) was added. The reaction mixture was heated to 120° C., stirred at this temperature overnight, allowed to cool to rt and diluted with acetonitrile. The resulting precipitate was collected by vacuum filtration and dried to provide 11 g of the title compound. tR: 1.80 min (LC-MS 2); ESI-MS: 414 [M+H]+ (LC-MS 2). The reaction mixture was heated to 120° C. stirred at this temperature overnight to cool to rt The resulting precipitate was collected by vacuum filtration dried

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-amino-5-chloro-benzonitrile (2.4 g, 15.7 mmol), 4-chloro-2-methyl-benzaldehyde (2.4 g, 15.7 mmol) and 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (2.9 g, 15.7 mmol) in acetic acid (15 mL) was stirred at 120° C. for 16 h. The reaction mixture was allowed to cool to rt, concentrated, diluted with acetonitrile (15 mL), and stirred for 4 h at rt. The resulting precipitate was collected by vacuum filtration and dried to afford 1.8 g of the title compound. tR: 6.50 min (HPLC 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.27 (hexane/EtOAc, 1:1). to cool to rt concentrated diluted with acetonitrile (15 mL) stirred for 4 h at rt The resulting precipitate was collected by vacuum filtration dried

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-amino-5-chloro-benzonitrile (2.4 g, 15.7 mmol), 4-chloro-2-methyl-benzaldehyde (2.4 g, 15.7 mmol) and 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (2.9 g, 15.7 mmol) in acetic acid (15 mL) was stirred at 120° C. for 16 h. The reaction mixture was allowed to cool to rt, concentrated, diluted with acetonitrile (15 mL), and stirred for 4 h at rt. The resulting precipitate was collected by vacuum filtration and dried to afford 1.8 g of the title compound. tR: 6.50 min (HPLC 2); ESI-MS: 429 [M+H]+ (LC-MS 2); Rf=0.27 (hexane/EtOAc, 1:1). to cool to rt concentrated diluted with acetonitrile (15 mL) stirred for 4 h at rt The resulting precipitate was collected by vacuum filtration dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3,4-difluoro-aniline (1.8 g, 14.2 mmol), 4-chloro-benzaldehyde (2.0 g, 14.2 mmol) and 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (2.6 g, 14.2 mmol) acetic acid (10 mL) was refluxed overnight. The reaction mixture was allowed to cool to rt and diluted with acetonitrile. The resulting precipitate was collected by vacuum filtration and dried to afford 3.1 g of the title compound. tR: 5.89 min (HPLC 2); ESI-MS: 390 [M−H]− (LC-MS 2). was refluxed overnight The resulting precipitate was collected by vacuum filtration dried

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-chloro-2-fluoro-aniline (428 mg, 2.94 mmol) and 2,4-dichloro-benzaldehyde (515 mg, 2.94 mmol) was heated to 110° C., stirred for 4 h, allowed to cool to rt, and diluted with toluene (5 mL). A solution of the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (615 mg, 2.94 mmol) in dioxane (5 mL) and acetic acid (0.17 mL) were added. The resulting mixture was refluxed for 15 h, allowed to cool to rt and diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→95:5) to provide 660 mg of the title compound. tR: 1.40 min (LC-MS 1); ESI-MS: 443.8 [M+H]+ (LC-MS 1). to cool to rt The resulting mixture was refluxed for 15 h to cool to rt The aqueous layer was separated extracted with EtOAc The combined organic extracts were washed with brine dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→95:5)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-chloro-2-fluoro-aniline (428 mg, 2.94 mmol) and 2,4-dichloro-benzaldehyde (515 mg, 2.94 mmol) was heated to 110° C., stirred for 4 h, allowed to cool to rt, and diluted with toluene (5 mL). A solution of the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (615 mg, 2.94 mmol) in dioxane (5 mL) and acetic acid (0.17 mL) were added. The resulting mixture was refluxed for 15 h, allowed to cool to rt and diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→95:5) to provide 660 mg of the title compound. tR: 1.40 min (LC-MS 1); ESI-MS: 443.8 [M+H]+ (LC-MS 1). to cool to rt The resulting mixture was refluxed for 15 h to cool to rt The aqueous layer was separated extracted with EtOAc The combined organic extracts were washed with brine dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→95:5)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-chloro-2-fluoro-aniline (10.9 g, 75 mmol) and 4-chloro-benzaldehyde (10.0 g, 71 mmol) was heated to 120° C., stirred for 18 h, allowed to cool to rt, and diluted with toluene (50 mL). A mixture of the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (14.8 g, 71 mmol) in dioxane (50 mL) and acetic acid (4.1 mL, 71 mmol) was added. The resulting mixture was refluxed for 18 h, allowed to cool to rt, diluted with EtOAc, and washed twice with an aqueous solution of NaHCO3 and brine. The crude product, obtained after drying and concentration, was triturated with EtOAc/hexane to provide 14 g of the title compound. tR: 5.23 min (HPLC 1); ESI-MS: 408 [M+H]+ (LC-MS1). to cool to rt was added The resulting mixture was refluxed for 18 h to cool to rt washed twice with an aqueous solution of NaHCO3 and brine The crude product, obtained after drying concentration was triturated with EtOAc/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3-chloro-2-fluoro-aniline (0.70 g, 4.8 mmol), 4-chloro-2-methyl-benzaldehyde (0.74 g, 4.8 mmol) and the sodium salt of 5-methyl-2,4-dioxo-hexanoic acid ethyl ester (1.0 g, 4.8 mmol) in acetic acid (6 mL) was refluxed for 3 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→9:1), followed by crystallization from EtOAc/hexane, to provide 426 mg of the title compound. tR: 5.47 min (HPLC 1); ESI-MS: 422 [M+H]+ (LC-MS 1). extracted twice with ethyl acetate The combined organic extracts were washed with brine dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography (CH2Cl2/MeOH, 1:0→9:1) followed by crystallization from EtOAc/hexane